Comparative Study of Neurosurgical Complications of Thalassemia and Sickle Cell Disease

Léon Boukassa¹, Didace Massamba Miabaou², Hugues Brieux Ekouélé Mbaki¹, Sinclair Brice Kinata Bambino¹, Olivier Brice Ngackosso¹, Rel Boukaka Kala¹, Gédéon Colin Thouassa¹, Ruth Ibara Wamé¹

¹Department of Neurosurgery, Brazzaville University Hospital Center, Brazzaville, Republic of the Congo.
²Department of General Surgery, Brazzaville University Hospital Center, Brazzaville, Republic of the Congo.

DOI: 10.4236/ojmn.2024.143020                

Abstract

Introduction: Sickle cell disease and thalassemia are the most frequent hemoglobinopathies. During their evolution, they present certain complications, among which are two neurosurgical emergencies, namely spontaneous cranial epidural hematoma and non traumatic radiculo-medullary compression, with some particularities for each. Method: In order to highlight these particularities, we compared the characteristics of these two complications, from a number of publications reported between 2000 and 2021. Results: Sickle cell disease was complicated by spontaneous cranial epidural hematoma. Forty-two cases were reported, the mean age was 14.7 years (2 - 21 years) and the sex ratio was 6.4. The clinical presentation combined, in a non-traumatic context, signs of intracranial hypertension with those of neurological focalization. Neuroimaging showed epidural-type collection, often frontal and parietal in location. The incriminating mechanisms were ischemia, hemorrhage and extra medullary hematopoiesis. The treatment was surgical. Non traumatic radiculo-medullary was the complication of thalassemia. Of the 77 cases reported, the mean age was 27.5 years (9 - 66 years) and the sex ratio was 4.1. The lesions were epidural with a clear thoracic predominance and resulted from extra marrow hematopoiesis. Treatment included: hypertransfusion, radiotherapy, hydroxyurea and surgery. Vital and functional prognosis were globally satisfactory when the management was rapid. Conclusion: Cranial and spinal epidural lesions, respective complications of sickle cell disease and thalassemia, result from similar mechanisms. Their prognosis depends on the rapidity of management.

Keywords

Hemoglobinopathy, Sickle Cell Disease, Thalassemia, Spontaneous Epidural Hematoma, Extra Marrow Hematopoiesis, Slow Marrow Compression

1. Introduction

Sickle cell disease and thalassemia, initially described in Africa and the Mediterranean basin respectively [1], now represent major medical challenges worldwide. These conditions are caused by mutations in the beta-globin gene for sickle cell disease and in the synthesis of the alpha or beta chains of hemoglobin for thalassemia.

Due to the disruption of hemoglobin production, patients suffer from chronic anemia, to which the body responds with chronic stimulation of erythropoiesis, which has its drawbacks. Indeed, this reactive erythropoiesis occurs not only in the organs usually involved in this process but also in those that have lost this function after embryonic life, as well as in unusual spaces [2] [3]. This latter situation involves “abnormal” or “ectopic” hematopoiesis, which, depending on its location, can be termed juxta-medullary or extramedullary. Often asymptomatic, it can lead to certain complications [4]. Among these are two neurosurgical emergencies: spontaneous cranial epidural hematoma (SCEDH) and Non-traumatic radiculo-medullary compression (NTRMC), which add to stroke, a common neurological complication of these hemoglobinopathies. These conditions, whose diagnoses have been refined thanks to new medical imaging techniques, are increasingly reported in the medical literature.

Despite their common origin, these neurosurgical emergencies display certain differences in their clinical and paraclinical expressions. Understanding these complications is necessary to improve their management within the group of these complex hemoglobinopathies.

It is with this aim that we sought to report these particularities, comparing the epidemiological, diagnostic, therapeutic, and evolutionary characteristics of these two complications, based on cases published in the literature and our own.

2. Methodology

In order to compare the neurosurgical complications of these two haemoglobinopathies, we searched, over a period of 21 years (January 2000 to December 2021), using search engines (Pub Med, Google, Google Scholar), for articles published, in French or English, on this subject. The search terms were: complications of haemoglobinopathies, extramedullary haematopoiesis, juxtamedullary haematopoiesis, epidural haematoma, extradural haematoma, thalassaemia, sickle cell anaemia, non-traumatic spinal cord compression, cauda equina compression. To avoid duplication, we analysed each article carefully, looking at the parameters of age, sex, year and place of publication, location of the lesion, treatment carried out and outcome. When all these elements were identical between two cases, they were counted once. Other locations of ectopic haematopoiesis were excluded, as were cases discovered at autopsy.

We added to this number those of our team who had not yet been published. From these publications, we extracted and recorded in an Excel table, the epidemiological, clinical and paraclinical, therapeutic and evolutionary data for each of these two haemoglobinopathies (Table 1). As not all publications contained the same information, the number of patients found per parameter studied was noted. As this was not a meta-analysis or a review of the literature on the neurosurgical complications of thalassemia or sickle cell disease, we compared the complications of these two haemoglobinopathies on each parameter.

Table 1. Comparative table of neurosurgical complications in sickle cell disease and thalassaemia.

Items	Sickle cell disease	Thalassaemia
Type of haemoglobinopathy	SS, FS	Minor, Major
Sex ratio	6,4	4,1
Mean Age (Year)	14.7 [2 - 21]	27.5 [9 - 66]
Type of complication	SCEDH	NTCRM
Investigation	TDM/IRM	IRM
Mechanism	Ischaemia Coagulopathy Ectopic haematopoiesis	Ectopic haematopoiesis
Treatment	Transfusion Surgery	Transfusion Radiotherapy Chemotherapy Surgery
Evolution (letality)	16,2%	None

3. Results

Over the 21 years that constitute our study period, 95 publications were identified with a total of 118 cases. Spontaneous cranial epidural hematomas (SCEDH) were reported in 31 articles for a total of 40 cases. This number increases to 41 cases, when we add the last case observed in our department. Concerning the second complication, we counted 64 articles in which 77 cases of Non-traumatic radiculo-medullary compression (NTRMC) were published.

Spontaneous cranial epidural haematoma [4]-[34]

Spontaneous cranial epidural haematomas (41 cases) were exclusively a complication of sickle cell disease in its SS (97.3%) and FS (26.7%) forms. The patients had a mean age of 14.7 years [2 - 21 years] and were predominantly male (sex ratio: 6.4). They were seen in consultation within a mean time of 55.6 h or 2.3 days with extremes ranging from 4 h to 168 h. The clinical picture was made, in a non-traumatic context, of headaches that were considered as part of the diffuse algic picture of vaso-occlusive crises. They were associated with neurological focal signs in 80% of cases. Neuroimaging, including computed tomography (CT) and/or magnetic resonance imaging (MRI), was reported in 34 cases. This not only showed the haematoma and its location, but also allowed us to suspect the mechanism behind its formation. The location was unilateral in 70.3% of cases (47.6% on the right, 21.7% on the left) and bilateral in 29.7%. They were frontal in 42.4%, parietal in 36.7%, fronto-parietal in 15.5% and occipital and posterior cerebral fossa in 2.7% each. The mechanism of occurrence of these hematomas, reported in 15 cases, was ischemia in 73.4%, coagulopathy and extra medullary hematopoiesis in 13.3% each. The treatment performed in all patients was transfusion (conservative) alone in 25.9% or associated with surgery in 74.1%. The latter resulted in a good outcome in 83.8% of cases and a lethal outcome in 16.2%.

Non-traumatic radiculo-medullary compression [1] [3] [35]-[94]

Non-traumatic radiculo-medullary compression (NTRMC) (77 cases) complicated thalassemia. These were intermediate thalassemias in 17 cases (including 5 cases of E thalassemia), thalassemias major in 11 cases. Associations of thalassemia and Lepore hemoglobin in 2 cases and thalassemia and sickle cell disease in one case had been reported. The average age of the patients was 27.5 years [9 - 45 years] with again, a male predominance (sex ratio = 4.1). They were seen in consultation with a mean delay of 93.2 days [3 - 360 days] for a spinal cord compression syndrome. They had all undergone an MRI, the results of which were reported in 72 patients. The compressive lesion was epidural, localized to a single spinal region in 83.3% of cases and to more than one region in 16.7% of cases. The lesions localized to a single region were mostly in the thoracic portion (76.4%). This same thoracic segment was often involved in multi-regional localizations with the cervical, lumbar and/or sacral segments.

At the end of this assessment, several therapeutic modalities were used. These were radiotherapy for which the doses and number of sessions were not always reported, hypertransfusion, surgery (laminectomy + removal of compressive epidural tissue), and hydroxyurea chemotherapy (drug treatment). Treatment using one or more of these procedures was reported in 62 patients. Regarding single treatments (50% of cases), radiotherapy alone, with its 17.6% of cases, was the most used. It was followed by hypertransfusion (13% patients), surgery (11.3%) and chemotherapy (8.1%). As for combinations, transfusion + radiotherapy and transfusion + surgery were used in 8 cases each. The combinations of drug treatment + radiotherapy and drug treatment + transfusion were reported in 3 cases each. Transfusion, surgery and radiotherapy were combined in 4 cases. Other combinations were also used (4 cases). Spontaneous recovery was also reported. The clinical evolution, apart from some neurological sequelae reported, was good in all cases.

4. Comments

This study is not a meta-analysis or a review of the literature on the neurosurgical complications of thalassemia or sickle cell disease. It compares the epidemiolgic, clinical, therapeutic and evolutionary aspects of two neurosurgical complications of these two most frequent hemoglobinopathies. This explains the non-exhaustive nature of the publications made on these subjects. Nevertheless, the numbers obtained allowed us to make this comparison. The period of this study was chosen somewhat because it corresponds to that of the generalization of new medical imaging techniques (CT scan and nuclear magnetic resonance imaging) in African countries south of the Sahara.

Thus, during the period from 2000 to 2021 (21 years), we found 95 articles published on the neurosurgical complications of these two hemoglobinopathies, namely sickle cell disease and thalassemia. These were SCEDH for sickle cell disease and NTRMC for thalassemia. These publications were mainly case reports. The largest series, for sickle cell disease complications, was 6 cases and for thalassemia 5 cases.

SCEDH were described in SS homozygous sickle cell patients and very rarely in the FS form. Intermediate forms (including E-Thalassemia) and major forms of thalassemia were the ones most complicated by NTRMC, but they were also encountered during the associations thalassemia + hemoglobin Lepore and thalassemia + sickle cell disease. They mainly affected young adult boys for thalassemia and adolescent boys for sickle cell disease.

The consultation time was shorter (2.3 days on average) for SCEDH and longer for NTRMC (93.2 days on average). These are, in fact, two neurosurgical emergencies with different immediate consequences. SCEDH remains an acute condition with a rapid clinical course and a risk of lethal evolution, whereas spinal cord compression is often slow to develop. It is more likely to be a functional disease.

The clinical signs for these non-traumatic or SCEDH combined those of intracranial hypertension (frequent) with signs of neurological focalization. In some cases a disturbance of consciousness was noted. The headache, sometimes the only sign of this intracranial hypertension, was often considered as part of the vaso-occlusive manifestations. In the absence of other neurological signs, this isolated headache probably explains the delay in diagnosis in some patients. The spinal cord compression syndrome was the classic clinical picture of this complication of thalassemia and was sometimes the revealing manifestation of this thalassemia [92].

The lesions were located in the epidural space in both cases. At the cranial level, the EDH presented as a peri-cerebral effusion in the form of a biconvex lens, like those of traumatic origin. The density or signal of the effusion depended on the duration of the lesion's evolution. Unilateral localizations were the most frequent with a predominance in frontal and parietal regions. MRI remains, even in this context, the paraclinical examination of choice in radiculo-medullary compressions. It showed dorsal epidural lesions that were hypo- or iso-signal with enhancement after injection of gadolinium [92] or iso or discretely hypersignal on T1 and T2 weighted sequences [75]. The thoracic spinal location, alone or associated with other locations, was the most frequent. The predominance of thoracic spinal location is thought to result either from extension of hematopoietic tissue through the proximal costal tubercles or adjacent vertebral bodies, or from development of hematopoietic tissue from branches of the intercostal veins, or from both mechanisms [89]. Root compression may also be observed, due to the same mechanisms [91]. Extramedullary hematopoiesis may involve the vertebral body, the epidural space, or both structures, resulting in radiculo-medullary compression. This lesion of ectopic hematopoiesis was found in one or more spinal segments but also in other organs which, for the circumstance, remembered their hematopoietic activity during embryonic life [2].

The MRI also gives arguments in favor of the mechanisms that were multiple in the occurrence of SEDH, namely: ischemic, hemorrhagic or by extramedullary hematopoiesis [28]. The latter was the only mechanism incriminated in NTRMC. These mechanisms also explain the epidural location of these lesions, this space being the first one that separates the bone from the cranial or spinal contents.

Therapeutically, SCEDH is a condition that responds to surgical treatment, when arguments based on thickness, mass effect and involvement indicate it. In cases of low thickness, absence of mass effect and non-existence of involvement, conservative treatment can be chosen. This was the case with our last patient. In the case of NTRMC, several therapeutic modalities were reported. They ranged from hypertransfusion regimen to radiotherapy, surgery and chemotherapy. In spite of the decision tree proposed by Haïdar [15] in this therapeutic management, the indications seemed to depend on the habits of the teams or on the decision of the multidisciplinary consultation. For patients who were seen in the neurosurgery department as a first line treatment and whose thalassemia was not known [92], or for those who had presented a rapid clinical deterioration, surgical treatment was indicated immediately, because of the functional emergency constituted by the spinal cord compression. This treatment has the advantage of providing operative material whose pathological examination makes it possible to make a definite diagnosis of this ectopic hematopoiesis by showing a polymorphic cellular infiltrate containing erythroblastic myeloid cells, lymphocytes, plasma cells, megakaryocytes and megakaryoblasts [1] [92].

This treatment had allowed to observe, in SHED, a cure in 83.8% and a mortality of 16.2%. For NTRMC, all cases had a good evolution, sometimes with neurological sequelae.

5. Conclusion

SHED and NTRMC are rare but serious complications of sickle cell disease and thalassaemia respectively. Ectopic haematopoiesis, which is the consequence of the physiological response to chronic anaemia, when it gives rise to a neurosurgical complication, is expressed differently in sickle cell disease and thalassaemia. It is therefore necessary to take this into account when monitoring patients with these haemoglobinopathies, as these are complications whose course is well known and does not take into account the context in which they occur.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References

[1]	Salehi, S.A., Koski, T. and Ondra, S.L. (2004) Spinal Cord Compression in Beta-Thalassemia: Case Report and Review of the Literature. Spinal Cord, 42, 117-123.[CrossRef] [PubMed]
[2]	Delicou, S. (2014) Extramedullary Haemopoiesis in Hemoglobinopathies. Journal of Hematology & Transfusion, 5, Article 1066.
[3]	Malik, M., Pillai, L.S., Gogia, N., Puri, T., Mahapatra, M., Sharma, D.N., et al. (2007) Paraplegia Due to Extramedullary Hematopoiesis in Thalassemia Treated Successfully with Radiation Therapy. Haematologica, 92, e28-e30.[CrossRef] [PubMed]
[4]	Affo, C., Baccar, L.S., Bosquet, A. and Mahe, I. (2021) Hémoglobinopathies constitutionnelles et compression médullaire chronique: Quel lien? La Revue de Médecine Interne, 42, A371.[CrossRef]
[5]	Azhar, M.J. (2010) Extradural Hemorrhage: A Rare Complication and Manifestation of Stroke in Sickle Cell Disease. Oman Medical Journal, 25, e017.[CrossRef] [PubMed]
[6]	Arends, S., Coebergh, J.A., Kerkhoffs, J.L., van Gils, A. and Koppen, H. (2011) Severe Unilateral Headache Caused by Skull Bone Infarction with Epidural Haematoma in a Patient with Sickle Cell Disease. Cephalalgia, 31, 1325-1328.[CrossRef] [PubMed]
[7]	Salman, Y., Abiola, A., Okezie, K., Oladele, A. and Babatola, B. (2012) Spontaneous Epidural Haematoma in Sickle Cell Anaemia: Case Report and Literature Review. Journal of Surgical Technique and Case Report, 4, 135-137.[CrossRef] [PubMed]
[8]	Banerjee, C., Yowtak, J., Fridlyand, D. and Alleyne Jr., C. (2018) Acute Spontaneous Intracranial Epidural Haematoma and Disseminated Intravascular Coagulation in a Paediatric Sickle Cell Patient. BMJ Case Reports, 2018, bcr-2018-224504.[CrossRef] [PubMed]
[9]	Bölke, E. and Scherer, A. (2011) Sickle Cell Disease. Canadian Medical Association Journal, 184, E201.[CrossRef] [PubMed]
[10]	Chaurasiya, M., Bhardwaj, S. and Naik, D. (2021) Can Spontaneous Bifrontal Extradural Haematoma Be a Sole Presentation in Previously Undiagnosed Sickle Cell Disease? A Rare Case Report and Literature Review. Interdisciplinary Neurosurgery, 25, Article ID: 101230.[CrossRef]
[11]	Dahdaleh, N.S., Lindley, T.E., Kirby, P.A., Oya, H. and Howard, M.A. (2009) A “Neurosurgical Crisis” of Sickle Cell Disease. Journal of Neurosurgery: Pediatrics, 4, 532-535.[CrossRef] [PubMed]
[12]	Eyenga, V., Ngah, E., Ngowe, M., Ze Minkande, J., Tchokoteu, P.F. and Sossou, M. (2001) Lettre à l’éditeur. Une complication neurochirurgicale rare de la drépanocytose: L’hématome extra dural spontané. Médecine d’Afrique noire, 48, 378-380.
[13]	Gajjar, R. and Gupta, P. (2015) Spontaneous Extradural Hematoma: A Rare Neurological Crisis in Sickle Cell Disease. IOSR Journal of Dental and Medical Sciences, 14, 94-96.
[14]	Hafidi, H., Basar, A., Dellamonica, J., Domergue, R. and Levraut, J. (2009) Hématome sous-dural aigu spontané chez un enfant de dix ans atteint de drépanocytose. Journal Européen des Urgences, 22, 24-26.[CrossRef]
[15]	Haidar, S., Ortiz-Neira, C., Shroff, M., Gilday, D. and Blaser, S. (2004) Intracranial Involvement in Extramedullary Hematopoiesis: Case Report and Review of the Literature. Pediatric Radiology, 35, 630-634.[CrossRef] [PubMed]
[16]	Hamm, J., Rathore, N., Lee, P., LeBlanc, Z., Lebensburger, J., Meier, E.R., et al. (2016) Cranial Epidural Hematomas: A Case Series and Literature Review of This Rare Complication Associated with Sickle Cell Disease. Pediatric Blood & Cancer, 64, e26237.[CrossRef] [PubMed]
[17]	Hettige, S., Sofela, A., Bassi, S. and Chandler, C. (2015) A Review of Spontaneous Intracranial Extradural Hematoma in Sickle-Cell Disease. Acta Neurochirurgica, 157, 2025-2029.[CrossRef] [PubMed]
[18]	Ilhan, N., Acipayam, C., Aydogan, F., Atci, N., Ilhan, O., Coskun, M., et al. (2014) Orbital Compression Syndrome Complicated by Epidural Hematoma and Wide Cephalohematoma in a Patient with Sickle Cell Disease. Journal of American Association for Pediatric Ophthalmology and Strabismus, 18, 189-191.[CrossRef] [PubMed]
[19]	Iversen, P.O., Jacob, M., Makame, J., Abisay, M., Yonazi, M., Schuh, A., et al. (2019) A Massive Extradural Hematoma in Sickle Cell Disease and the Importance of Rapid Neuroimaging. Case Reports in Hematology, 2019, Article ID: 1742472.[CrossRef] [PubMed]
[20]	Kalala Okito, J.P., Van Damme, O. and Calliauw, L. (2004) Are Spontaneous Epidural Haematoma in Sickle Cell Disease a Rare Complication? A Report of Two New Cases. Acta Neurochirurgica, 146, 407-410.[CrossRef] [PubMed]
[21]	Komarla, R., Soares, B.P., Chern, J.J. and Milla, S.S. (2018) Spontaneous Epidural Hematoma Secondary to Bone Infarction in Sickle Cell Anemia: Case Report. Journal of Neurosurgery: Pediatrics, 22, 18-21.[CrossRef] [PubMed]
[22]	Lee, C.M., Salzman, K.L., Blumenthal, D.T. and Gaffney, D.K. (2005) Intracranial Extramedullary Hematopoiesis: Brief Review of Response to Radiation Therapy. American Journal of Hematology, 78, 151-152.[CrossRef] [PubMed]
[23]	Mishra, S., Senapati, S., Gouda, A., Behera, S. and Patnaik, A. (2017) Spontaneous Extradural and Subgaleal Hematoma: A Rare Neurosurgical Crisis of Sickle Cell Disease. Asian Journal of Neurosurgery, 12, 47-50.[CrossRef] [PubMed]
[24]	Naran, A.D. and Fontana, L. (2001) Sickle Cell Disease with Orbital Infarction and Epidural Hematoma. Pediatric Radiology, 31, 257-259.[CrossRef] [PubMed]
[25]	Tokpa, A., Bah, A., Derou, L. and N’dri Oka, D. (2015) Spontaneous Intracranial Extradural Hematoma in Sickle Cell Disease. Journal of Neurological Surgery Reports, 76, e97-e99.[CrossRef] [PubMed]
[26]	Page, C., Gardner, K., Height, S., Rees, D.C., Hampton, T. and Lay Thein, S. (2013) Nontraumatic Extradural Hematoma in Sickle Cell Anemia: A Rare Neurological Complication Not to Be Missed. American Journal of Hematology, 89, 225-227.[CrossRef] [PubMed]
[27]	Patra, S., Mishra, S. and Das, S. (2012) A Rare Case of Spontaneous Bilateral Extradural Hematoma in a Sickle Cell Disease Child. Journal of Pediatric Neurosciences, 7, 77-78.[CrossRef] [PubMed]
[28]	Saha, B. and Saha, A. (2019) Spontaneous Epidural Hemorrhage in Sickle Cell Disease, Are They All the Same? A Case Report and Comprehensive Review of the Literature. Case Reports in Hematology, 2019, Article ID: 8974580.[CrossRef] [PubMed]
[29]	Sangle, S., Lohiya, R., Karne, S. and Chugh, A. (2011) Spontaneous Epidural Hematoma: A Rare Complication of Sickle Cell Anemia. Neurology India, 59, 301-302.[CrossRef] [PubMed]
[30]	Serarslan, Y., Aras, M., Altaş, M., Kaya, H. and Urfalı, B. (2014) Non-traumatic Spontaneous Acute Epidural Hematoma in a Patient with Sickle Cell Disease. Neurocirugía, 25, 128-131.[CrossRef] [PubMed]
[31]	Taher, A., Isma’eel, H. and Cappellini, M.D. (2006) Thalassemia Intermedia: Revisited. Blood Cells, Molecules, and Diseases, 37, 12-20.[CrossRef] [PubMed]
[32]	Taher, A., Musallam, K.M. and Cappellini, M.D. (2009) Thalassaemia Intermedia: an Update. Mediterranean Journal of Hematology and Infectious Diseases, 1, e2009004.[CrossRef] [PubMed]
[33]	Nasiri, A., Takroni, S., Ahmed, E. and Alkharras, R. (2021) Spontaneous Epidural Hematoma: A Case Report of Rare Crisis of Sickle Cell Disease. Journal of Family Medicine and Primary Care, 10, 428-4289.[CrossRef] [PubMed]
[34]	Tomboravo, C., Rajaonarison Ny Ony, L.H.N., Andrianarimanitra, H.U., Rakoto Alison, O.A. and Ahmad, A. (2019) Hématome extra-dural: Une complication rare de la drépanocytose. Sang Thrombose Vaisseaux, 31, 29-31.
[35]	Al-Habib, H. and Hadzikaric, N. (2007) Spinal Cord Compression Due to Intraspinal Extramedullary Hematopoiesis in Thalassemia Intermedia. Neurosciences, 12, 261-264.
[36]	Aliberti, B., Patrikiou, A., Terentiou, A., Frangatou, S. and Papadimitriou, A. (2001) Spinal Cord Compression Due to Extramedullary Haematopoiesis in Two Patients with Thalassaemia: Complete Regression with Blood Transfusion Therapy. Journal of Neurology, 248, 18-22.[CrossRef] [PubMed]
[37]	Alorainy, I.A., Al-Asmi, A.R. and del Carpio, R. (2000) MRI Features of Epidural Extramedullary Hematopoiesis. European Journal of Radiology, 35, 8-11.[CrossRef] [PubMed]
[38]	Ameri, A.A., Bagheri, M.H., Jalal, S.J. and Habibzadeh, F. (2003) Spinal Cord Compression Secondary to Extramedullary Hematopoiesis in Thalassemia. Iranian Journal of Radiology, 1, 8-11.
[39]	Batti, H., Khiari Mrabet, H., Nagi, S., Kallel, M. and Mrabet, A. (2011) Compression médullaire par de multiples foyers d’érythropoïèse extramédullaire au cours d’une drépanothalassémie. Revue Neurologique, 167, 861-863.[CrossRef] [PubMed]
[40]	Ben Ammar, L., Ferjani, H., Maatallah, K., et al. (2020) Spinal Cord Compression by Extramedullary Hematopoiesis in β-Thalassemia Major. Clinical Case Reports, 8, 1433-1436.
[41]	Boussaa, H., Kaffel, D., Maatallah, K., Lassoued Ferjani, H. and Hamdi, W. (2021) A Rare Cause of Lumbar Nerve Root Compression: Extramedullary Hematopoiesis in a Patient with Thalassemia Major. Clinical Case Reports, 9, e04119.[CrossRef] [PubMed]
[42]	Boyacigil, S., Ali, A., Ardiç, S. and Yüksel, E. (2002) Epidural Extramedullary Haemopoiesis in Thalassaemia. Australasian Radiology, 46, 180-182.[CrossRef] [PubMed]
[43]	Brunéteau, G., Fénelon, G., Khalil, A., Kanfrer, A. and Girot, R. (2000) Compression médullaire par hématopoièse ectopique chez un patient atteint de béta-thalassémie. Revue Neurologique, 156, 510-513.
[44]	Bukhari, S., Junaid, M. and Rashid, M. (2016) Thalassemia, Extramedullary Hematopoiesis, and Spinal Cord Compression: A Case Report. Surgical Neurology International, 7, S148-S152.[CrossRef] [PubMed]
[45]	Chehal, A., Aoun, E., Koussa, S., Skoury, H., Koussa, S. and Taher, A. (2003) Hypertransfusion: A Successful Method of Treatment in Thalassemia Intermedia Patients with Spinal Cord Compression Secondary to Extramedullary Hematopoiesis. Spine, 28, E245-E249.[CrossRef] [PubMed]
[46]	Chiam, Q. and Lau, K. (2007) Extramedullary Haematopoiesis in Thalassaemia Major Causing Spinal Cord Compression. Australasian Radiology, 51, 168-171.[CrossRef] [PubMed]
[47]	Chourmouzi, D., Pistevou-Gompaki, K., Plataniotis, G., Skaragas, G., Papadopoulos, L. and Drevelegas, A. (2001) MRI Findings of Extramedullary Haemopoiesis. European Radiology, 11, 1803-1806.[CrossRef] [PubMed]
[48]	Cianciulli, P., Caravita di Toritto, T., Sorrentino, F., Sergiacomi, L., Massa, A. and Amadori, S. (2000) Hydroxyurea Therapy in Paraparesisand Cauda Equina Syndrome Due to Extramedullary Haematopoiesis in Thalassaemia: Improvement of Clinicaland Haematological Parameters. European Journal of Haematology, 64, 426-429.[CrossRef] [PubMed]
[49]	Darole, P., Sundar, U., Kuchekar, N. and Karre, A. (2019) Unusual Presentation of Extramedullary Haematopoiesis in a Young Boy. BMJ Case Reports, 12, e227199.[CrossRef] [PubMed]
[50]	Dragean, C.A., Duquesne, L., Theate, I., Ghaye, B. and Coche, E.E. (2011) Extramedullary Haemopoiesis and Spinal Cord Compression. The Lancet, 377, 251.[CrossRef] [PubMed]
[51]	Duque, S.G., Jureschke, F.R. and Leal, R.G. (2019) Compresión medular con paraparesia reversible en paciente con ß-talasemia. Neurología, 34, 270-272.[CrossRef] [PubMed]
[52]	El Bahri-Ben, F., Zaouachi, N., Fredj, M., Ben, S. and Mrabet, A. (2003) Un nouveau cas de compression médullaire secondaire à une bêta-thalassémie. Revue Neurologique, 159, 574-576.
[53]	Emamhadi, M. and Alizadeh, A. (2012) Effect of Hypertransfusion on Extramedullary Hematopoietic Compression Mass in Thalassemia Major: A Case Report. Iranian Journal of Radiology, 9, 154-156.[CrossRef] [PubMed]
[54]	Esfandbod, M. and Malekpour, M. (2010) Thalassemia and Spinal Cord Compression in Pregnancy. Canadian Medical Association Journal, 182, E798.[CrossRef] [PubMed]
[55]	Fareed, S., Soliman, A., De Sanctis, V., Kohla, S., Soliman, D., Khirfan, D., Tambuerello, A., Talaat, M., Nashwan, A., Caparrotti, P. and Yassin, M.A. (2017) Spinal Cord Compression Secondary to Extramedullary Hematopoiesis: A Rareness in a Young Adult with Thalassemia Major. Acta Biomedica, 88, 237-242.
[56]	Gamberini, M.R., Fortini, M. and De Sanctis, V. (2004) Paraplegia Due to Spinal Cord Compression by Extramedullary Erythropoietic Tissue in a Thalassaemia Intermedia Patient with Gynecomastia Secondary to Cirrhosis: Successful Treatment with Hydroxyurea. Pediatric Endocrinology Reviews, 2, 316-318.
[57]	Ghieda, U., Elshimy, M. and El Beltagi, A.H. (2013) Progressive Spinal Cord Compression Due to Epidural Extramedullary Hematopoiesis in Thalassemia Intermedia. The Neuroradiology Journal, 26, 111-117.[CrossRef] [PubMed]
[58]	Ghosh, A., Das, D., Sarkar, D., Devi, L.G. and Ghosh, B. (2005) Acute Reversible paraplegia—An Interesting Haematological Problem. Journal, Indian Academy of Clinical Medicine, 6, 73-75.
[59]	Goerner, M., Gerull, S., Schaefer, E., Just, M., Sure, M. and Hirnle, P. (2008) Painful Spinal Cord Compression as a Complication of Extramedullary Hematopoiesis Associated with β-Thalassemia Intermedia. Strahlentherapie und Onkologie, 184, 224-226.[CrossRef] [PubMed]
[60]	Gologan, R., Lupescu, I., Bujor, L., et al. (2005) Thoracic Spinal Cord Compression Secondary to Extramedullary Haematopoiesis in Thalassaemia Intermedia Successfully Treated by Local Radiotherapy and Hydroxyurea: A Case Report and Review of the Literature. HAEMA, 8, 667-674.
[61]	Gupta, P., Shaikh, S., Goyal, R. and Gupta, D. (2021) Extramedullary Hematopoiesis Presenting with Thoracic Spinal Cord Compression in a Young Adult with Thalassemia Major: A Case Report. Journal of Pediatric Neurosciences, 16, 303-306.[CrossRef] [PubMed]
[62]	Hamdi, W., Azzouz, D., Ghannouchi, M., Kaffel, D., Mahjoub, S., Ben Rhomdane, N., et al. (2009) Compression médullaire par un foyer d’hématopoïèse périrachidien au cours d’une β-thalassémie intermédiaire. Revue du Rhumatisme, 76, 479-481.[CrossRef]
[63]	Hashmi, M., Guha, S., Sengupta, P., Basu, D., Baboo, S. and Neha, N. (2014) Thoracic Cord Compression by Extramedullary Hematopoiesis in Thalassemia. Asian Journal of Neurosurgery, 9, 102-104.[CrossRef] [PubMed]
[64]	İleri, T., Azk, F., Ertem, M., Uysal, Z. and Gozdasoglu, S. (2009) Extramedullary Hematopoiesis with Spinal Cord Compression in a Child with Thalassemia Intermedia. Journal of Pediatric Hematology/Oncology, 31, 681-683.[CrossRef] [PubMed]
[65]	Ismail, I.I., Massoud, F., Alexander, K.J. and Al-Hashel, J.Y. (2019) Compressive Dorsal Myelopathy Secondary to Extramedullary Hematopoiesis in a Thalassemic Patient. Case Reports in Neurological Medicine, 2019, Article ID: 5827626.[CrossRef] [PubMed]
[66]	Judy, B.F., Jin, Y. and Sciubba, D.M. (2021) Extramedullary Hematopoiesis Causing Spinal Cord Compression. World Neurosurgery, 149, 51-52.[CrossRef] [PubMed]
[67]	Karimi, M., Zarei, T. and Pishdad, P. (2018) Extramedullary Hematopoiesis in a Patient with Transfusion Dependent β-Thalassemia Presenting with Cord Compression. Iranian Journal of Blood and Cancer, 10, 28-30.
[68]	Keikhaei, B., Zandian, K. and Rahim, F. (2008) Existence of Cord Compression in Extramedullary Hematopoiesis Due to β Thalassemia Intermedia. Hematology, 13, 183-186.[CrossRef] [PubMed]
[69]	La, V.T., Diatte, M., Gaston, J., Dick, D., Sweiss, R. and Pakbaz, Z. (2018) Spinal Cord Compression Due to Extramedullary Hematopoiesis in a Patient with E-β-Thalassemia Managed without Radiation or Surgery. Journal of Community Hospital Internal Medicine Perspectives, 8, 246-249.[CrossRef] [PubMed]
[70]	Lopes, R.R.S., Cardoso, L.S. and Onishi, F. (2020) Spinal Cord Compression Due to Extramedullary Hematopoiesis in β-thalassemia. Arquivos de Neuro-Psiquiatria, 78, 663-664.[CrossRef] [PubMed]
[71]	Maazoun, F., Gellen Dautremer, J., Boutekadjirt, A., Pissard, S., Habibi, A., et al. (2016) Hématopoïèse extra-médullaire symptomatique au cours des β-thalassémies: Étude rétrospective monocentrique. La Revue de Médecine Interne, 37, 5-12.[CrossRef] [PubMed]
[72]	Michel, L., Auffray-Calvier, E., Raoul, S. and Derkinderen, P. (2008) Spinal Cord Compression Secondary to Extra Medullary Hematopoiesis. Clinical Neurology and Neurosurgery, 110, 1073.[CrossRef] [PubMed]
[73]	Montero, A., Sancho, S., Hervas, A., et al. (2004) Spinal Cord Compression Due to β-Thalassemia Intermedia: Results of Re-Irradiation. Radiotherapy and Oncology, 71, S41.
[74]	Nasr Ben Ammar, C., Belaïd, A., Kochbati, L. and Maalej, M. (2007) Hématopoïèse extramédullaire: À propos de deux cas. Cancer/Radiothérapie, 11, 490-494.[CrossRef] [PubMed]
[75]	Niggemann, P., Krings, T., Hans, F. and Thron, A. (2005) Fifteen-Year Follow-Up of a Patient with β Thalassaemia and Extramedullary Haematopoietic Tissue Compressing the Spinal Cord. Neuroradiology, 47, 263-266.[CrossRef] [PubMed]
[76]	Pathirage, L.P.M.M.K., Wijeweera, I., Jayasinghe, C., Jayabahu, S. and Wickramasinghe, H.R. (2016) Episodic Spastic Paraparesis Successfully Treated with Unaided Blood Transfusions: A Case Report. BMC Research Notes, 9, Article No. 123.[CrossRef] [PubMed]
[77]	Peinavandi, M.Q. and Khoddami, M. (2006) Paravertebral Extramedullary Hematopoiesis in a Pregnant Thalassemic Patient: A Case Report. Iranian Journal of Pathology, 1, 131-134.
[78]	Perker, S.C., Elebisoy, M. and Akkoll Bezircioglu, H. (2003) Paraplegia Due to Extramedullary Hematopoiesis in the Thalassemia Intermedia. Turkish Journal of Medical Sciences, 33, 341-344.
[79]	Phupong, V., Uerpairojkij, B. and Limpongsanurak, S. (2000) Spinal Cord Compression: A Rareness in Pregnant Thalassemic Woman. Journal of Obstetrics and Gynaecology Research, 26, 117-120.[CrossRef] [PubMed]
[80]	Sahu, N., Pradhan, P., Das, N., Dash, K. and Senapati, U. (2019) Extramedullary Hematopoiesis in Case of Hemoglobin E β-Thalassemia: An Unusual Cause of Paraplegia. Iraqi Journal of Hematology, 8, 48-51.[CrossRef]
[81]	Rahim, F., Keikhaei, B., Zandian, K. and Soltani, A. (2008) Diagnosis and Treatment of Spinal Cord Compression Secondary to Extramedullary Hematopoiesis in Patients with β-Thalassemia Intermedia. Journal of Clinical and Diagnostic Research, 2, 643-647.
[82]	Rey, J., Gagliano, R., Christides, et al. (2001) Compression médullaire par des foyers d’hématopoïèse extra médullaire au cours de la thalassémie. La Presse Médicale, 30, 1351-1353.
[83]	Ruo Redda, M.G., Allis, S., Reali, A., Bartoncini, S., Roggero, S., Anglesio, S.M., et al. (2014) Complete Recovery from Paraparesis in Spinal Cord Compression Due to Extramedullary Haemopoiesis in β-Thalassaemia by Emergency Radiation Therapy. Internal Medicine Journal, 44, 409-412.[CrossRef] [PubMed]
[84]	Saghafi, M., Shirdel, A. and Lari, S.M. (2005) Extramedullary Hematopoiesis with Spinal Cord Compression in β-Thalassemia Intermedia. European Journal of Internal Medicine, 16, 596-597.[CrossRef] [PubMed]
[85]	Savini, P. (2011) Paraparesis Induced by Extramedullary Haematopoiesis. World Journal of Radiology, 3, 82-84.[CrossRef] [PubMed]
[86]	Soman, S., Tharadara, G.D., Chhatrala, N. and Jain, S. (2016) A Case Report of Extramedullary Haematopoeisis in Lumbosacral Region Presenting as Cauda Equina Syndrome. International Journal of Spine Surgery, 10, Article 25.[CrossRef] [PubMed]
[87]	Subahi, E.A., Abdelrazek, M. and Yassin, M.A. (2020) Spinal Cord Compression Due to Extramedullary Hematopoiesis in Patient with β Thalassemia Major. Clinical Case Reports, 9, 405-409.[CrossRef] [PubMed]
[88]	Tai, S.M., Chan, J.S.H., Ha, S.Y., Young, B.W.Y. and Chan, M.S.M. (2006) Successful Treatment of Spinal Cord Compression Secondary to Extramedullary Hematopoietic Mass by Hypertransfusion in a Patient with Thalassemia Major. Pediatric Hematology and Oncology, 23, 317-321.[CrossRef] [PubMed]
[89]	Tan, T., Tsao, J. and Cheung, F. (2002) Extramedullary Haemopoiesis in Thalassemia Intermedia Presenting as Paraplegia. Journal of Clinical Neuroscience, 9, 721-725.[CrossRef] [PubMed]
[90]	Tantawy, A.A.G., Adly, A.A.M., Mahdy, S.A.R. and Kamel, G.Z. (2009) Spinal Cord Compression and Extramedullary Hematopoiesis in Young Egyptian β-Thalassemia Patients. Hemoglobin, 33, 448-462.[CrossRef] [PubMed]
[91]	Tsitsopoulos, P., Zevgaridis, D., Tsitsopoulos, P., Tsonidis, C., Anagnostopoulos, I. and Marinopoulos, D. (2007) Lumbar Nerve Root Compression Due to Extramedullary Hemopoiesis in a Patient with Thalassemia: Complete Clinical Regression with Radiation Therapy. Journal of Neurosurgery: Spine, 6, 156-160.[CrossRef] [PubMed]
[92]	Varlet, G., N’dri Oka, D., Drogba, K.L., Haïdara, A., Zunon-Kipré, Y. and Ba Zézé, V. (2010) β-thalassémie intermédiaire compliquée d’une compression médullaire. Étude de trois observations et méta-analyse. Neurochirurgie, 56, 315-323.[CrossRef] [PubMed]
[93]	Wahab, S., Khan, R., Ahmad, K., Wahab, A. and Ahmad, I. (2013) Extramedullary Haematopoiesis Causing Spinal Cord Compression in a Thalassemia Intermedia Patient. Nepalese Journal of Radiology, 2, 81-85.[CrossRef]
[94]	Yathiraj, P.H., Singh, A., Vidyasagar, S., Varma, M. and Mamidipudi, V. (2017) Excellent and Durable Response to Radiotherapy in a Rare Case of Spinal Cord Compression Due to Extra-Medullary Hematopoiesis in β-Thalassemia Intermedia: Case Report and Clinicoradiological Correlation. Annals of Palliative Medicine, 6, 195-199.[CrossRef] [PubMed]